NARCOLEPSY -Scientific Discussion

Narcolepsy

Epidemiology:

• Prevalence ~1 in 2000 (US)–Comparable to multiple sclerosis, greater than cystic fibrosis

• •Men and women affected equally

• •Age at onset–Can present at any age–Majority 15-30 years of age–6% prior to 10 years of ageOvereem et al. J ClinNeurophysiol. 2001;18:78.

• Key Issues

• •Less than 50% currently diagnosed

• •Diagnosis delayed >10 years after onset

• •Chronic disorder, manageable, not curable •Profound impact on quality of life

• •Requires multiple pharmacologic and nonpharmacologic interventions  

Thorpy. Sleep Med.2001;2:5.

 

Genetics and Narcolepsy

•Human genetic susceptibility

–Most cases are sporadic

–Familial forms

–HLA-DQB1*0602 association

•Canine narcolepsy

•Knockout mouse model of narcolepsy

Mignot. Neurology. 1998;50(suppl 1):S16.

 

HLA Disease Comparison

Disorder                                  HLA Antigen              Relative Risk

Ankylosis spondylitis                   B27                          69.1

Juvenile rheumatoid arthritis        B27                            3.9

Ulcerative colitis                          B5                             3.8

Psoriasis                                     Cw6                           7.5

Multiple sclerosis                        DR2                            6.0

Narcolepsy                                  DR2                         130.0

RR = (% Antigen positive patients) (% Antigen negative controls)(% Antigen negative patients) (% Antigen positive controls) Courtesy of M.P. Biber, MD. 2002.

 

Neurochemical Abnormalities

•Excessive daytime sleepiness

–?Dopaminergic transmission

•Cataplexy

–?Monoaminergic tone (dopaminergic

and/or adrenergic)

–?Cholinergic hypersensitivity (M2)

Nishino and Mignot. Prog Neurobiol. 1997;52:27.Reid et al. Brain Res. 1996;733:83.

Hypocretin

•Hypothalamic peptides

–Localized in the dorsolateral hypothalamus

–Wide projections throughout the brain

–Projections found in the spinal column

•Peptide neurotransmitters

–Arousal

–Locomotion

–Metabolism

–Increase blood pressure/heart rate

Peyron et al. J Neurosci. 1998;18:9996. Moore et al. Arch Ital Biol. 2001;139:195. Silber and Rye. Neurology. 2001;56:1616.

 

 Excessive Daytime Sleepiness(EDS)

•Chronic pervasive fatigue

–All day, every day

•Sleep attacks

–Irresistible, overwhelming urges to sleep

•Naps

–Commonly short (eg, 10-20 min), but can be longer

•Automatic behavior

•Occurs in 100% of patients with narcolepsy

Overeem et al. J Clin Neurophysiol. 2001;18:78. Bassetti and Aldrich. Neurol Clin. 1996;14:545.

Cataplexy

•REM–related phenomenon

•Sudden hypotonia or atonia of voluntary muscles triggered by emotions

–Attacks range from a fleeting sensation of weakness

to complete paralysis and powerlessness

–Duration is usually <2 minutes

•Medically stable, with consciousness and ocular movement preserved

•Occurs in most narcolepsy patients; considered pathognomonic

Bassetti and Aldrich. Neurol Clin. 1996;14:545; Krahn et al. Mayo Clinic Proc.2001;76:185; Anic-Labat et al. Sleep. 1999;22:77.

 Fragmented Nocturnal Sleep

•Severe disruption of nocturnal sleep may occur in up to 90% of patients with narcolepsy

–Frequent awakenings

–Fragmented circadian rhythms

–Early onset REM periods

–Sleep intruding into usual waking hours

Guilleminault. Narcolepsy syndrome. In: Principles and Practice of Sleep Medicine. 1994;Bassettiand Aldrich. Neurol Clin. 1996;14:545.

Levels of Certainty for Diagnosis

 (from most certain to least certain)

•EDS and unequivocal cataplexy

•Isolated, unequivocal cataplexy without EDS

•Narcolepsy with positive MSLT and questionable cataplexy

•Narcolepsy with positive MSLT and no cataplexy

•Suspected narcolepsy –No MSLT or negative MSLT (8-min mean sleeplatency but <2 SOREMPs) and questionable cataplexy

•EDS of unknown etiology without cataplexy

•EDS due to other diagnosed sleep disorders

Mitler. An Introduction to Narcolepsy. National Sleep Foundation Slide Kit.

Narcolepsy Treatment Goals

•Reduce excessive sleepiness

•Control cataplexy and other associated REM-related symptoms (sleep paralysis, hypnagogic and hynopompic hallucinations)

•Improve nighttime sleep

•Reduce psychosocial problems

Krahn et al. Mayo Clin Proc. 2001;76:185.

Traditional ManagementApproaches

•Excessive daytime sleepiness

–Structured nocturnal sleep

–Naps: scheduled and PRN

–Stimulants or wake-promoting agents

•Cataplexy

–Antidepressants (TCA or SSRI)

•Sleep fragmentation

–Sleep hygiene

–Hypnotics (limited utility)

•General

–Personal and family counseling

–Support

Parkes. Sleep. 1994;17:S93; Mitler et al. Sleep. 1994;17:352; Daly and Yoss. Narcolepsy. In: Handbook of Clinical Neurology. 1974;15:836; Bassetti and Aldrich. Neurol Clin. 1996;14:545; Mamelak et al. Sleep. 1986;9:285.

Mechanism of Stimulants in the Treatment of Excessive Daytime Sleepiness

•Amphetamines, methylphenidate, and pemoline

–CNS stimulants of major midbrain dopamine systems

–Indirect sympathomimetics increase synaptic cleft

levels of monoamines by enhancing release and blocking

reuptake of

•Norepinephrine

•Dopamine

•Serotonin

Mitler et al. Sleep. 1994;17:352.

Mechanism of Modafinil in theTreatment of Excessive Daytime Sleepiness

•Modafinil is chemically unrelated to CNS stimulants

–Activation of hypothalamic regions

–Does not act directly through dopaminergic pathways

–May indirectly inhibit GABA release

Physician’s Desk Reference. 2001; Ferraro et al. Neuropsychopharmacology. 1999;20:346;

Chemelli et al. Cell. 1999;98:437; Edgar and Seidel. J Pharmacol Exp Ther. 1997;283:757.

Sodium Oxybate:

Efficacy Conclusions

•Only therapy that improves the 3 major symptoms

of narcolepsy: cataplexy, EDS, nighttime sleep

•Cataplexy

–Only medication indicated for cataplexy

–Up to 90% median reduction in cataplexy attacks

–Established long-term efficacy

–No acute rebound on withdrawal

•Excessive Daytime Sleepiness (EDS)

–Sustained decrease in sleepiness demonstrated up to 12 months

–Increases ability to stay awake

–Incremental improvement beyond stimulant therapy

•Consolidates nighttime sleep

–?Stage 3 and 4 sleep

–?Delta power

–?Nighttime awakenings

•No evidence of tolerance with long-term use

•Improves physician overall impression of clinical status

•Improves patient perception of quality of life

Narcolepsy Conclusion

•A disorder of sleepiness with REM phenomena

•Major impact on QOL

•Low to absent hypocretin levels

•Diagnosis made by PSG and MSLT

•Sleepiness is treated by stimulants and wake-promoting agents

•Cataplexy has traditionally been treated by TCAs

and SSRIs

•A new multisymptom treatment approach with

sodium oxybate